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Efficacy and safety of eculizumab in childhood atypical hemolytic uremic syndrome in Japan

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Abstract

Background

Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease with frequent progression to end-stage renal disease (ESRD). Eculizumab, a humanized anti-C5 monoclonal antibody targeting the activated complement pathway, has recently been introduced as a novel therapy against aHUS. We, therefore, investigated the efficacy and safety of eculizumab in Japanese pediatric patients.

Methods

We retrospectively analyzed clinical course and laboratory data of the first ten children with aHUS treated with eculizumab nationwide.

Results

Seven patients were resistant to plasma therapy and three were dependent on it. Causative gene mutations were found in five patients. Two patients had anti-complement factor H autoantibody. Three patients had a family history of thrombotic microangiopathy (TMA). After initiation of eculizumab, all patients immediately achieved hematological remission and could successfully discontinue plasma therapy. The median periods to normalization of platelet count, lactate dehydrogenase levels and disappearance of schistocytes were 5.5, 17 and 12 days, respectively. Nine patients recovered their renal function and the median period to terminate renal replacement therapy (RRT) was 3 days. However, two patients progressed to ESRD and required chronic RRT at the last observation. No patients had a relapse of TMA under regular eculizumab therapy. No serious adverse events occurred during the follow-up period.

Conclusions

Eculizumab is efficacious and well-tolerated therapy for children with aHUS. Although pathogenic mutations could not be detected in five patients, all patients showed immediate normalization of hematological abnormalities, strongly suggesting complement-related aHUS. This prompt hematological amelioration can become an indicator for therapeutic efficacy of eculizumab. However, appropriate indications and optimal duration of the treatment remain unclear.

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References

  1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87.

    Article  CAS  PubMed  Google Scholar 

  2. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392–400.

    Article  CAS  PubMed  Google Scholar 

  4. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kavanagh D, Goodship T. Genetics and complement in atypical HUS. Pediatr Nephrol. 2010;25:2431–42.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013;8:554–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26:41–57.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Verhave JC, Wetzels JF, van de Kar NC. Novel aspects of atypical haemolytic uraemic syndrome and the role of eculizumab. Nephrol Dial Transplant. 2014;29:iv131–41.

    Article  PubMed  Google Scholar 

  9. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643–57.

    Article  CAS  PubMed  Google Scholar 

  10. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81.

    Article  CAS  PubMed  Google Scholar 

  11. Fakhouri F, Delmas Y, Provot F, Barbet C, Karras A, Makdassi R, et al. Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases. Am J Kidney Dis. 2014;63:40–8.

    Article  CAS  PubMed  Google Scholar 

  12. Wong EK, Goodship TH, Kavanagh D. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol. 2013;56:199–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:544–6.

    Article  CAS  PubMed  Google Scholar 

  14. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J Kidney Dis. 2012;59:707–10.

    Article  CAS  PubMed  Google Scholar 

  15. Besbas N, Gulhan B, Karpman D, Topaloglu R, Duzova A, Korkmaz E, et al. Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab. Pediatr Nephrol. 2013;28:155–8.

    Article  PubMed  Google Scholar 

  16. Christmann M, Hansen M, Bergmann C, Schwabe D, Brand J, Schneider W. Eculizumab as first-line therapy for atypical hemolytic uremic syndrome. Pediatrics. 2014;133:e1759–63.

    Article  PubMed  Google Scholar 

  17. Sawai T, Nangaku M, Ashida A, Fujimaru R, Hataya H, Hidaka Y, et al. Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society. Clin Exp Nephrol. 2014;18:4–9.

    Article  CAS  PubMed  Google Scholar 

  18. Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, et al. Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease. Clin Exp Nephrol. 2014;18:626–33.

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34:571–90.

    CAS  PubMed  Google Scholar 

  20. Fan X, Yoshida Y, Honda S, Matsumoto M, Sawada Y, Hattori M, et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol. 2013;54:238–46.

    Article  CAS  PubMed  Google Scholar 

  21. Administration USFaD. Prescribing information for Soliris. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf.

  22. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687–96.

    Article  PubMed  Google Scholar 

  23. Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, et al. An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol. 2014;29:1967–78.

    Article  PubMed  Google Scholar 

  24. Kim J, Waller S, Reid C. Eculizumab in atypical haemolytic-uraemic syndrome allows cessation of plasma exchange and dialysis. Clin Kidney J. 2012;5:34–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Povey H, Vundru R, Junglee N, Jibani M. Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis. Clin Nephrol. 2014;82:326–31.

    Article  CAS  PubMed  Google Scholar 

  26. Hillmen P, Muus P, Roth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162:62–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lewis LA, Ram S. Meningococcal disease and the complement system. Virulence. 2014;5:98–126.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Takahashi H, Kuroki T, Watanabe Y, Tanaka H, Inouye H, Yamai S, et al. Characterization of Neisseria meningitidis isolates collected from 1974 to 2003 in Japan by multilocus sequence typing. J Med Microbiol. 2004;53:657–62.

    Article  CAS  PubMed  Google Scholar 

  29. Tanimoto T, Kusumi E, Hosoda K, Kouno K, Hamaki T, Kami M. Concerns about unapproved meningococcal vaccination for eculizumab therapy in Japan. Orphanet J Rare Dis. 2014;9:48.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy. Pediatr Nephrol. 2011;26:1919–20.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ardissino G, Testa S, Possenti I, Tel F, Paglialonga F, Salardi S, et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases. Am J Kidney Dis. 2014;64:633–7.

    Article  CAS  PubMed  Google Scholar 

  32. Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the following co-investigators for their contributions to this study: Kenji Ishikura (Tokyo Metropolitan Children’s Medical Center), Koichi Kamei (National Center for Child Health and Development), Tomohiro Udagawa (Tokyo Medical and Dental University), Tomohito Takimoto, Masamitsu Shirozu and Manao Nishimura (Kyushu University). We also appreciate Yoko Yoshida (Nara Medical University) and Toshiyuki Miyata (National Cerebral and Cardiovascular Center) for performing hemolytic assays, anti-CFH antibody analysis and genetic mutation screening. Alexion Pharmaceuticals, Inc. provided eculizumab on compassionate grounds to seven patients in this study until eculizumab received approval for the indication of aHUS in Japan.

Conflict of interest

Potential financial conflicts of interest. Patent royalties: Yoshihiro Fujimura (Alfresa Pharma), Honoraria: Shuichi Ito (Alexion Pharma), Research funding: Yoshihiro Fujimura (Alexion Pharma). The other authors have declared that no conflicts of interest exist.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8583, Japan

    Naoko Ito, Hidetoshi Takada & Toshiro Hara

  2. Department of Pediatric Nephrology, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan

    Hiroshi Hataya, Yasuhiro Yoshida, Chikako Terano & Wataru Kubota

  3. Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Ken Saida & Shuichi Ito

  4. Department of Pediatrics, Nagano Red Cross Hospital, 5-22-1 Wakasato, Nagano, 380-8582, Japan

    Yoshiro Amano

  5. Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan

    Yoshihiko Hidaka

  6. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Yaeko Motoyoshi

  7. Department of Pediatric Nephrology, Hiroshima Prefectural Hospital, 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan

    Toshiyuki Ohta

  8. Department of Pediatrics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Tadashi Iwasa

  9. Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara, 634-8521, Japan

    Yoshihiro Fujimura

  10. Department of Pediatrics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan

    Shuichi Ito

Authors
  1. Naoko Ito
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  2. Hiroshi Hataya
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  8. Yasuhiro Yoshida
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  11. Wataru Kubota
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  12. Hidetoshi Takada
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  13. Toshiro Hara
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  14. Yoshihiro Fujimura
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  15. Shuichi Ito
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Corresponding author

Correspondence to Shuichi Ito.

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Ito, N., Hataya, H., Saida, K. et al. Efficacy and safety of eculizumab in childhood atypical hemolytic uremic syndrome in Japan. Clin Exp Nephrol 20, 265–272 (2016). https://doi.org/10.1007/s10157-015-1142-y

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  • DOI: https://doi.org/10.1007/s10157-015-1142-y

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